Gγ4 Inhibitors

Chemical inhibitors of Gγ4 function through various mechanisms to disrupt the normal signaling pathways in which Gγ4 participates. Gossypol, for example, binds to G-protein coupled receptors (GPCRs), altering their conformation which in turn inhibits the GPCR-mediated activation of G-proteins, including Gγ4. Pertussis toxin operates by ADP-ribosylating the Gαi subunit of heterotrimeric G-proteins, which prevents the interaction between Gαi and Gγ4, effectively inhibiting the function of Gγ4. Similarly, cholera toxin catalyzes the ADP-ribosylation of Gαs subunits. This modification leads to the persistent activation of Gαs, which disrupts the regulatory cycles that would normally involve Gγ4, thereby inhibiting its function.

Other inhibitors target different components of the G-protein signaling pathway to inhibit Gγ4. NF449 is a selective Gαs inhibitor that prevents Gαs from binding to Gγ4, disrupting the Gαs-Gβγ dimer necessary for Gγ4 activity. YM-254890 specifically inhibits Gαq function, which in turn disrupts the Gαq-Gβγ complex formation necessary for Gγ4 activity. Suramin antagonizes GPCRs to inhibit the receptor-mediated activation of G-proteins, which includes Gγ4. BIM-46187 inhibits G-protein-coupled receptor signaling, thus reducing the activation of associated G-proteins and inhibiting Gγ4 participation in signal transduction. CCG-4986 selectively inhibits the Regulator of G-protein Signaling 4 (RGS4), which in turn leads to inhibited Gα-Gγ4 interactions and subsequent inhibition of Gγ4 function. AG 1478 blocks receptor tyrosine kinases that are involved in the activation of G-protein signaling pathways, thus indirectly inhibiting Gγ4 function. Tertiapin-Q binds to and inhibits GIRK channels that are modulated by Gβγ subunits of G-proteins, indirectly affecting Gγ4 by interfering with Gβγ-mediated signaling. Lastly, U73122 inhibits phospholipase C, which is vital for GPCR signaling, consequently preventing downstream signaling that depends on G-protein activation and thus indirectly inhibiting Gγ4 function.